Inder J. Chopra

Ontogenesis of hypothalamic--pituitary--thyroid function and metabolism in man, sheep, and rat.

Publisher Summary This chapter discusses the maturation of hypothalamus and thyroid function. It also discusses the maturation of the neurovascular communication system between the hypothalamus and pituitary in a newborn rat. It is a progressive process continuing throughout the period of hypothalamic maturation. By 17 days of gestation, the pituitary gland is surrounded by a capillary network and separated from the brain by a thin layer of mesenchyme and capillaries—this is referred to as the supra-tuberal plexus, or the secondary plexus of the portal system. The chapter illustrates Triiodothyronine (T3) production rates in rats at different times after birth. In the illustration, T3 production rates, per 100 body weight are plotted as mean and SEM. The general pattern of ontogenesis of the hypothalamic-pituitarythyroid system in the human, sheep, and rat species is similar. The timing of the several stages relative to parturition differs in the rat. Human and sheep fetuses are delivered toward the end of the stage of development of neuroendocrine control and early in the period of maturation of tissue metabolic systems. In contrast, the rat is delivered soon after completion of embryogenesis of the thyroid and pituitary glands early in stage II maturation of the hypothalamus.

Thyroid function in nonthyroidal illnesses.

Alterations in thyroid physiology and thyroid function tests occur in some patients with nonthyroidal illnesses. Low concentrations of serum triiodothyronine (T3) usually occur in nonthyroidal illnesses and are attributable largely to reduced extrathyroidal conversion of thyroxine (T4) to T3. Concentrations of serum total T4 may be low, normal, or high; alterations in serum binding of T4 explain the abnormality in most cases. Concentrations of serum reverse T3 are usually high because metabolic clearance is reduced. Whether patients with nonthyroidal illnesses with low T4 or T3, or both, are hypothyroid is uncertain; concentrations of free T4 have been estimated as low, normal, or high using different methods. Serum thyroid-stimulating hormone is typically normal. Low concentrations of T3 or T4, or both, in nonthyroidal illnesses may have a homeostatic significance. Low serum concentrations of T4 correlate with poor prognosis in nonthyroidal illnesses. Inhibitors of thyroid hormone binding and phagocytosis are present in normal tissues. Leakage of the inhibitors into the circulation may lower serum concentrations of T4 on one hand and compromise critical host defenses on the other.

Safety and Hemodynamic Effects of Intravenous Triiodothyronine in Advanced Congestive Heart Failure

Most patients with advanced congestive heart failure have altered thyroid hormone metabolism. A low triiodothyronine level is associated with impaired hemodynamics and is an independent predictor of poor survival. This study sought to evaluate safety and hemodynamic effects of short-term intravenous administration of triiodothyronine in patients with advanced heart failure. An intravenous bolus dose of triiodothyronine, with or without a 6- to 12-hour infusion (cumulative dose 0. 1 5 to 2.7 microg/kg), was administered to 23 patients with advanced heart failure (mean left ventricular ejection fraction 0.22 +/- 0.01). Cardiac rhythm and hemodynamic status were monitored for 12 hours, and basal metabolic rate by indirect calorimetry, echocardiographic parameters of systolic function and valvular regurgitation, thyroid hormone, and catecholamine levels were measured at baseline and at 4 to 6 hours. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.

Alterations in monodeiodination of iodothyronines in the fasting rat: effects of reduced nonprotein sulfhydryl groups and hypothyroidism.

Hepatic monodeiodination of thyroxine (T4), reverse triiodothyronine (rT3), and triiodothyronine (T3) are enzymic reactions that depend on tissue concentrations of sulfhydryl (SH) groups. Fasting in the rat is associated with low serum concentration of thyroid hormones (T4 and T3), a low rate of hepatic 5′-monodeiodination of T4, and low tissue concentrations of nonprotein SH (NP-SH) groups. This study describes the relationship between these various abnormalities and the effect of fasting on conversion of rT3 and T3 to 3,3′-diiodothyronine (3,3′-T2). Male Sprague-Dawley rats weighing 150–220 g were sacrificed after fasting for 0, 1, 2, and 4 days and iodothyronine monodeiodinations and total SH (T-SH) and NP-SH concentrations were quantified in liver homogenates. Hepatic T-SH concentration did not change appreciably during fasting. However, NP-SH levels decreased considerably at 1 day and then gradually recovered to or towards normal by 4 days of fasting. Hepatic NP-SH concentration in a representative experiment was 6.2 ± 0.20 μM/g in controls and 4.1 ± 0.49, 5.2 ± 0.36, and 6.9 ± 1.2 μM/g (mean ± SE) at 1, 2, and 4 days of fasting, respectively. On the other hand, T4-T3 converting activity (ng T3 produced/μg T4/geq tissue/hr) decreased progressively from 219 ± 15 in controls to 205 ± 18, 166 ± 6.7, (p < 0.005) and 149 ± 10 (p < 0.005) at 1, 2, and 4 days of fasting, respectively. Addition of dithiothreitol (DTT) to liver homogenates of 2-day (412 ± 15) and 4-day (397 ± 42) fasted rats did not render T3 production from T4 comparable to that in control animals (613 ± 76). When rats were treated with T4 (2 μg100 g body wt), changes in liver NP-SH still occurred as mentioned. However, hepatic T4-T3 conversion was reduced (193 ± 11 versus 352 ± 29, p < 0.005) only at 2 days when NP-SH was low, and it increased normally after addition of DTT (691 ± 26 versus 823 ± 74, NS). It was normal in absence (357 ± 67) and in presence (872 ± 68) of DTT at 4 days of fasting when NP-SH was normal. Monodeiodination of T3 to 3,3′-T2 was normal in fasting, whereas that of rT3 was low but normalized with DTT. The various data suggest that (1) low tissue NP-SH levels are important in causing the reduction in hepatic T4 5′-monodeiodination only early in fasting (subsequently, hypothyroidism is the key factor); and (2) inner ring monodeiodination of T3 is normal in fasting.

Serum thyroid hormone binding inhibitor in nonthyroidal illnesses

We have employed the recently developed competitive ligand binding assay (CLBA) to study thyroid hormone binding inhibitor (THBI) in ether extracts of sera of 25 patients admitted to the Medical Intensive Care Unit with a variety of nonthyroidal illnesses (NTI). THBI was detected in 60% (15/25) of patients using one sample/patient and in 88% (15/17) using multiple (two to six) samples from different days. Mortality rate and mean serum concentrations of total T4, total T3, and albumin were similar in THBI-positive and THBI-negative patients. There was a tendency for a higher frequency of low serum total T4 in THBI-positive (10/15) than in THBI-negative (3/10) patients but the difference was not statistically significant (P less than 0.1 by Chi square). However, the mean dialyzable fraction of T4 (DFT4 0.11 +/- 0.02%, n = 9 v 0.054 +/- 0.004%, n = 10) and DFT3 (0.54 +/- 0.05% v 0.40 +/- 0.032%) were both significantly (P less than 0.05) higher in THBI-positive patients than THBI-negative patients. There was a significant correlation between THBI and DFT4 (r = 0.55, P less than 0.02) or DFT3 (r = 0.54, P less than 0.02). Prior extraction of serum with ether reduced DFT4 in NTI patients with high baseline DFT4 but not in normal subjects or NTI patients with mildly abnormal baseline DFT4. Addition to a normal serum (0.1 mL) of evaporated ether extract of a pooled NTI serum (0.10- to 3.0-mL equivalent) increased DFT4 progressively from 0.025% to 0.14%. Similar extract of a pooled serum of normal subjects had little or no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in circulating estradiol-17 in male patients with Graves's disease.

Abstract Serum concentrations of estradiol-17β (E2), gonadotropins and long acting thyroid stimulator were studied in 10 consecutive male patients with active Gravess disease. Serum E2 was elevated in all patients before therapy. In two men with gynecomastia the concentrations were as high as those observed in normal women. The per cent dialyzable E2 was significantly reduced in hyperthyroid males as compared to normal males and was similar to that seen in eugonadal women; but the absolute concentration of unbound E2, evaluated in one prepubertal and five adult patients without gynecomastia, was elevated in four of the five adults. The mean serum concentrations of luteinizing and follicle-stimulating hormones were also higher in the hyperthyroid men than in normal men. Serum E2 fell gradually and consistently during effective treatment of hyperthyroidism with propylthiouracil. Neither the occurrence of gynecomastia nor the serum concentration of E2 correlated with serum concentration of long acting thyro...

Metabolism of 3,5,3'-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of 3,5,3'-triiodothyronine sulfate as a source of T3

ABSTRACTS: We have recently demonstrated that serum concentration of 3,5,3‘-triiodothyronine sulfate (T3S) is markedly elevated in the human newborn at a time when serum 3,5,3’-triiodothyronine (T3) is very low. The present study explores the ability of maternal (19–21 d pregnant) and near-term fetal Sprague-Dawley rat tissues to 1) monodeiodinate T3S and T3 in both the outer and the inner ring and 2) desulfate T3S to T3. Maternal liver microsomes metabolized T3S exceedingly efficiently (compare fetus p < 0.05). Eighty percent or more of T3S was consumed during its incubation with 360 μg/mL microsomes for 2 h. The majority of the consumption of T3S by adult liver microsomes occurred by its 5‘-monodeiodination to 1; little inner-ring monodeiodination to 3,3’-diiodothyronine was demonstrable. In fetal liver microsomes, however, over 75% of the substrate T3S remained unchanged after a 2-h incubation. T3 was metabolized similarly moderately by fetal and maternzl liver microsomes. Brain microsomes metabolized T3S poorly in both the mother and the fetus. Over 90% of substrate T3S remaned unchanged after a 2-h incubation in each case. Interestingly, brain microsomes metabolized T3 more rapidly than T3S (p < 0.05). In the fetus, desulfation of T3S to T3 was clearly evident only in microsoms from the liver and the brain; in the adult, it was plentiful in many tissues. Fetal liver and brain tissues metabolize T3S poorly, and both actively desulfate T3S to T3. These data and those indicating high serum T3S in the fetus suggest that T3S is a local source of T3 in critical tissues in the fetus and possibly in adults with the low T3 syndrome.

Thyroxine Inner Ring Monodeiodinating Activity in Fetal Tissues of the Rat

ABSTRACT: We studied thyroxine (T4) inner ring monodeiodinating activity (5-MA) in various tissues of fetal, maternal, and adult male rats. Tissue homogenates were incubated with 0.26 μM T4 in 0.1 M phosphate buffer (pH 7.4) containing 10 mM EDTA and 400 mM dithiothreitol (final volume 0.7 ml) for 10 min at 37° C; the 3,3‘,5’-triiodothyronine (rT3) generated was measured by radio-immunoassay of ethanol extracts of incubation mixture and the result was corrected for rT3 degradation during incubation. Compared to maternal tissues, T4 to rT3 5-MA in the 14-day-old fetus was increased about 70 times in skeletal muscle (mean ± SEM, velocity, 5.4 ± 0.9 versus 0.08 ± 0.01, pmol rT3/h/mg protein); ∼8 times in intestine (0.72 ± 0.17 versus 0.09 ± 0.03); and ∼4 times in cerebral cortex (19 ± 0.5 versus 4.5 ± 0.9), while it was similar in skin (3.2 ± 0.48 versus 2.6 ± 0.52). Hepatic T4 5-MA approximated 1.1 ± 0.63 in the 14-day-old fetus; it could not be measured reliably in maternal or 19-day fetal tissue because of extensive (>90%) degradation of rT3 during incubation. Relative to mother, T4 5-MA in 19-day fetal tissues was increased ∼30-fold in intestine, ∼20-fold in skeletal muscle, and ∼6-fold in cerebral cortex while it was similar in skin. The T4 5-MA in maternal rat tissues did not differ significantly from corresponding values in adult male rat, except skin, where it was lower in the mother rat (2.6 ± 0.52 versus 4.6 ± 0.61, p < 0.05). In summary, relative to adult tissues T4 5-MA is exceedingly active in several fetal tissues, most notably in skeletal muscle followed by intestine and cerebral cortex.

Gonadal Steroids and Gonadotropins in Hyperthyroidism

Gynecomastia occurs in about 20 to 40 per cent of men with hyperthyroidism. Serum concentrations of total estradiol-17beta, total testosterone, and luteinizing hormone are supranormal in these patients. Serum concentration of SHBG is also high in hyperthyroidism. This can explain the high serum testosterone, essentially completely but not the high serum estradiol-17beta; thus, whereas serum unbound testosterone is normal, serum unbound estradiol-17beta is above normal in hyperthyroid men. This balance in relative concentrations of unbound gonadal steroids is apparently quite favorable to the development of gynecomastia in hyperthyroidism. Increased peripheral tissue metabolism of androgens to estrogens seems to be the major factor responsible for high estradiol-17beta in hyperthyroidism; increased glandular secretion of estradiol-17beta may also be important. The mechanism of hypomenorrhea or amenorrhea in hyperthyroidism remains unclear. Changes in circulating estrogens, androgens, and luteinizing hormone in hyperthyroid women are similar to those in hyperthyroid men. The mid-cycle ovulatory peak of luteinizing hormone may be blunted in patients with scanty periods whereas it may be altogether absent in those with amenorrhea.

Effect of humic acids on thyroidal function

Humic substances (HS) have been implicated as environmental goitrogens. Increased prevalence of goiter has been recently noticed in the blackfoot disease endemic area on the southwest coast of Taiwan, where well water is rich in HS. This study investigated the in vivo effects of humic acids (HA) on the thyroid gland of rats and mice. Groups of mice and rats were fed regular or moderately iodine deficient (∼167 vs 700 μg I− per kg) chow and distilled water or HA water (1 mg/ml) for 3 or 4 months. Serum T4, T3, reverse T3, and/or TSH were measured by radioimmunoassay. Thyroidal 125I uptake was measured in mice at 2 h after injection of 1 μCi125I ip. Treatment of the rat with HA was associated with a significantly (p<0.05) reduced serum T4 without a change in other parameters of study. Treatment with low iodine diet was associated with a clear increase in serum T3 and a decrease in serum rT3. Rats treated with both HA and low iodine diet showed a significantly reduced serum T4, increased serum T3 and decreased serum rT3. In mice, treatment with low iodine diet significantly increased thyroidal 125I uptake and additional treatment with HA significantly enhanced the effect of low iodine diet. Treatment with HA did not influence thyroid weight of rats or mice given normal or iodine deficient diets. We conclude that HA per se do not induce goiter, but they may enhance the goitrogenic effect of low iodine.